Benzoxazolyl derivatives useful as 5-lipoxygenase inhibitors

ABSTRACT

The invention concerns a bicyclic heterocyclic derivative of the formula I ##STR1## wherein Q is an optionally substituted 9-membered bicyclic heterocyclic moiety containing 1 or 2 N&#39;s and optionally a further N, O or S heteroatom; 
     A 1  is a direct link to X 1  or (1-3C)alkylene; 
     X 1  is oxy, thio, sulphinyl, sulphonyl or imino; 
     Ar is optionally substituted phenylene or pyridylene; 
     R 1  is (1-4C)alkyl, (3-4C)alkenyl or (3-4C)alkynyl; and 
     R 2  and R 3  together form a group of the formula --A 2  --X 2  --A 3  -- which, together with the carbon atom to which A 2  and A 3  are attached, defines a ring having 5 to 7 ring atoms, wherein each of A 2  and A 3  is (1-3C)alkylene and X 2  is oxy, thio, sulphinyl or sulphonyl; 
     or a pharmaceutically-acceptable salt thereof. 
     The compounds of the invention are inhibitors of the enzyme 5-lipoxygenase.

This is a division of application Ser. No. 08/133,335, filed Oct. 8,1993, now U.S. Pat. No. 5,364,877, which is a divisional of applicationSer. No. 07/950,164 filed Sep. 24, 1992 (now U.S. Pat. No. 5,278,177);which is a divisional of application Ser. No. 07/717,501 filed Jun. 19,1991 (now U.S. Pat. No. 5,179,115).

This invention concerns novel bicyclic heterocyclic derivatives and moreparticularly novel bicyclic heterocyclic derivatives which areinhibitors of the enzyme 5-lipoxygenase (hereinafter referred to as5-LO). The invention also concerns processes for the manufacture of saidbicyclic heterocyclic derivatives and novel pharmaceutical compositionscontaining them. Also included in the invention is the use of saidbicyclic heterocyclic derivatives in the treatment of variousinflammatory and/or allergic diseases in which the direct or indirectproducts of 5-LO catalysed oxidation of arachidonic acid are involved,and the production of new medicaments for such use.

As stated above the bicyclic heterocyclic derivatives describedhereinafter are inhibitors of 5-LO, which enzyme is known to be involvedin catalysing the oxidation of arachidonic acid to give rise via acascade process to the physiologically active leukotrienes such asleukotriene B₄ (LTB₄) and the peptido-lipid leukotrienes such asleukotriene C₄ (LTC₄) and leukotriene D₄ (LTD₄) and various metabolites.

The biosynthetic relationship and physiological properties of theleukotrienes are summarised by G. W. Taylor and S. R. Clarke in Trendsin Pharmacological Sciences, 1986, 7, 100-103. The leukotrienes andtheir metabolites have been implicated in the production and developmentof various inflammatory and allergic diseases such as arthriticdiseases, asthma, allergic rhinitis, atopic dermatitis, psoriasis,cardiovascular and cerebrovascular disorders and inflammatory boweldisease. In addition the leukotrienes are mediators of inflammatorydiseases by virtue of their ability to modulate lymphocyte and leukocytefunction. Other physiologically active metabolites of arachidonic acid,such as the prostaglandins and thromboxanes, arise via the action of theenzyme cyclooxygenase on arachidonic acid.

We have now discovered that certain bicyclic heterocyclic derivativesare effective as inhibitors of the enzyme 5-LO and thus of leukotrienebiosyntheses. Thus, such compounds are of value as Therapeutic agents inthe treatment of, for example, allergic conditions, psoriasis, asthma,cardiovascular and cerebrovascular disorders, and/or inflammatory andarthritic conditions, mediated alone or in part by one or moreleukotrienes.

According to the invention there is provided a bicyclic heterocyclicderivative of the formula I (set out hereinafter)

wherein Q is a 9-membered bicyclic heterocyclic moiety containing one ortwo nitrogen heteroatoms and optionally containing a further heteroatomselected from nitrogen, oxygen and sulphur, which heterocyclic moietymay optionally bear one or two oxo or thioxo substituents and up to fourfurther substituents selected from halogeno, hydroxy, cyano, amino,(1-4C)alkyl, (1-4C)alkoxy, fluoro-(1-4C)alkyl, (1-4C)alkylamino,di-[(1-4C)alkyl]amino, amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl,di-[(1-4C)alkyl]amino-(1-4C)alkyl, phenyl and phenyl-(1-4C)alkyl, and

wherein said phenyl or phenyl-(1-4C)alkyl substituent may optionallybear a substituent selected from halogeno, (1-4C)alkyl and (1-4C)alkoxy;

wherein A¹ is a direct link to X¹ or is (1-3C)alkylene;

wherein X¹ is oxy, thio, sulphinyl, sulphonyl or imino;

wherein Ar is phenylene which may optionally bear one or twosubstituents selected from halogeno, hydroxy, amino, nitro, cyano,carbamoyl, ureido, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino,di-[(1-4C)alkyl]amino, fluoro-(1-4C)alkyl and (2-4C)alkanoylamino; or

Ar is pyridylene;

wherein R¹ is (1-4C)alkyl, (3-4C)alkenyl or (3-4C)alkynyl; and

wherein R² and R³ together form a group of the formula --A² --X² --A³ --which, together with the carbon atom to which A² and A³ are attached,defines a ring having 5 to 7 ring atoms, wherein A² and A³, which may bethe same or different, each is (1-3C)alkylene and X² is oxy, thio,sulphinyl or sulphonyl, and which ring may bear one, two or threesubstituents, which may be the same or different, selected from hydroxy,(1-4C)alkyl and (1-4C)alkoxy;

or wherein R¹ and R² together form a group of the formula --A² --X² --A³-- which, together with the oxygen atom to which A² is attached and withthe carbon atom to which A³ is attached, defines a ring having 5 to 7ring atoms, wherein A² and A³, which may be the same or different, eachis (1-3C)alkylene and X² is oxy, thio, sulphinyl or sulphonyl, and whichring may bear one, two or three (1-4C)alkyl substituents,

and wherein R³ is (1-4C)alkyl, (2-4C)alkenyl or (2-4C)alkynyl;

or a pharmaceutically-acceptable salt thereof.

The chemical formulae referred to herein by Roman numerals are set outfor convenience on a separate sheet hereinafter.

In this specification the generic term "alkyl" includes bothstraight-chain and branched-chain alkyl groups. However references toindividual alkyl groups such as "propyl" are specific for thestraight-chain version only and references to individual branched-chainalkyl groups such as "isopropyl" are specific for the branched-chainversion only. An analogous convention applies to other generic terms.

It is to be understood that, insofar as certain of the compounds of theformula I defined above may exhibit the phenomenon of tautomerism andany formula drawing presented herein may represent only one of thepossible tautomeric forms, the invention includes in its definition anytautomeric form of a compound of the formula I which possesses theproperty of inhibiting 5-LO and is not to be limited merely to any onetautomeric form utilised within the formulae drawings.

It is further to be understood that, insofar as certain of the compoundsof formula I defined above may exist in optically active or racemicforms by virtue of one or more substituents containing an asymmetriccarbon atom, the invention includes in its definition any such opticallyactive or racemic form which possesses the property of inhibiting 5-LO.The synthesis of optically active forms may be carried out by standardtechniques of organic chemistry well known in the art, for example bysynthesis from optically active starting materials or by resolution of aracemic form. Similarly, inhibitory properties against 5-LO may beevaluated using the standard laboratory techniques referred tohereinafter.

Suitable values for the generic terms referred to above include thoseset out below.

A suitable value for Q when it is a 9-membered bicyclic heterocyclicmoiety containing one or two nitrogen heteroatoms and optionallycontaining a further heteroatom selected from nitrogen, oxygen andsulphur is, for example, a benzo-fused heterocyclic moiety or ahydrogenated derivative thereof such as indolyl, indolinyl, isoindolyl,isoindolinyl, indolizinyl, benzimidazolyl, 2,3-dihydrobenzimidazolyl,1H-indazolyl, 2,3-dihydro-1H-indazolyl, benzoxazolyl,2,3-dihydrobenzoxazolyl, benzo[c]isoxazolyl, benzo[d]isoxazolyl,2,3-dihydrobenzo[d]isoxazolyl, benzothiazolyl,2,3-dihydrobenzothiazolyl, benzo[c]isothiazolyl, benzo[d]isothiazolyland 2,3-dihydrobenzo[d]isothiazolyl, or, for example, a pyrido-fusedheterocyclic moiety or a hydrogenated derivative thereof such as1H-pyrrolo[2,3-b]pyridyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridyl,1H-pyrrolo[2,3-c]pyridyl, 2,3-dihydro-1H-pyrrolo[2,3-c]pyridyl,1H-imidazo[4,5-b]pyridyl, 2,3-dihydro-1H-imidazo[4,5-b]pyridyl,1H-imidazo[4,5-c]pyridyl and 2,3-dihydro-1H-imidazo[4,5-c]pyridyl. Theheterocyclic moiety may be attached through any available positionincluding from either of the two rings of the bicyclic heterocyclicmoiety and including through an available nitrogen atom. Theheterocyclic moiety may bear a suitable substituent such as, forexample, a (1-4C)alkyl, di-[(1-4C)alkyl]amino-(1-4C)alkyl, phenyl orphenyl-(1-4C)alkyl substituent on an available nitrogen atom.

Suitable values for substituents which may be present on Q or Ar, or ona phenyl or phenyl-(1-4C)alkyl substituent on Q, include, for example:

halogeno: fluoro, chloro, bromo and iodo;

for (1-4C)alkyl: methyl, ethyl, propyl, isopropyl, butyl, isobutyl andsec-butyl;

for (1-4C)alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy;

for fluoro-(1-4C)alkyl: fluoromethyl, difluoromethyl, trifluoromethyl,2-fluoroethyl, 2,2,2-trifluoroethyl and pentafluoroethyl;

for (1-4C)alkylamino: methylamino, ethylamino, propylamino andbutylamino; and

for di-[(1-4C)alkyl]amino: dimethylamino, diethylamino anddipropylamino.

Suitable values for substituents which may be present on Q include, forexample:

for amino-(1-4C)alkyl: aminomethyl, 1-aminoethyl, 2-aminoethyl,2-aminopropyl and 3-aminopropyl;

for (1-4C)alkylamino-(1-4C)alkyl: methylaminomethyl, 2-methylaminoethyl,3-methylaminopropyl, ethylaminomethyl and 2-ethylaminoethyl;

for di-[(1-4C)alkyl]amino-(1-4C)alkyl: dimethylaminomethyl,2-dimethylaminoethyl, 3-dimethylaminopropyl, diethylaminomethyl and2-diethylaminoethyl;

for phenyl-(1-4C)alkyl: benzyl, phenethyl and 3-phenylpropyl.

A suitable value for A¹ when it is (1-3C)alkylene is, for example,methylene, ethylene or trimethylene.

A suitable value for Ar when it is phenylene is, for example,1,3-phenylene or 1,4-phenylene.

A suitable value for Ar when it is pyridylene is, for example, 3,5- or2,6-pyridylene.

A suitable value for a (2-4C)alkanoylamino substituent which may bepresent on Ar is, for example, acetamido, propionamido or butyramido.

A suitable value for R¹ when it is (1-4C)alkyl is, for example, methyl,ethyl, propyl or butyl; when it is (3-4C)alkenyl is, for example, allyl,2-butenyl or 3-butenyl; and when it is (3-4C)alkynyl is, for example,2-propynyl or 2-butynyl.

When R² and R³ together form a group of the formula --A² --X² --A--A³ --which, together with the carbon atom to which A² and A² are attached,defines a ring having 5 to 7 ring atoms then a suitable value for A² orA³, which may be the same or different, when each is (1-3C)alkylene is,for example, methylene, ethylene or trimethylene. Suitable values forthe substituents which may be present on said 5- to 7-membered ringinclude for example:for

for (1-4C)alkyl: methyl, ethyl, propyl, isopropyl, butyl and isobutyl;

for (1-4C)alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy.

When R¹ and R² together form a group of the formula --A² --X² --A³ --which together with the oxygen atom to which A² is attached and with thecarbon atom to which is attached, defines a ring having 5 to 7 ringatoms then a suitable value for A² A³, which may be the same ordifferent, when each is (1-3C)alkylene is, for example, methylene,ethylene or trimethylene. Suitable values for the (1-4C)alkylsubstituents which may be present on said 5- to 7-membered ring include,for example, methyl, ethyl, propyl, isopropyl and butyl.

A suitable value for R³ when it is (1-4C)alkyl is, for example, methyl,ethyl, propyl or butyl; when it is (2-4C)alkenyl is, for example, vinyl,allyl, 2-butenyl or 3-butenyl; and when it is (2-4C)alkynyl is, forexample, ethynyl, 2-propynyl or 2-butynyl.

A suitable pharmaceutically-acceptable salt of a compound of theinvention is, for example, an acid-addition salt of a compound of theinvention which is sufficiently basic, for example, an acid-additionsalt with, for example, an inorganic or organic acid, for examplehydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic,citric or maleic acid. In addition a suitablepharmaceutically-acceptable salt of a compound of the invention which issufficiently acidic is an alkali metal salt, for example a sodium orpotassium salt, an alkaline earth metal salt, for example a calcium ormagnesium salt, an ammonium salt or a salt with an organic base whichaffords a physiologically-acceptable cation, for example a salt withmethylamine, dimethylamine, trimethylamine, piperidine, morpholine ortris-(2-hydroxyethyl)amine.

Particular novel compounds of the invention are, for example, bicyclicheterocyclic derivatives of the formula I wherein

(a) Q is a 9-membered benzo-fused heterocyclic moiety containing onenitrogen heteroatom and optionally containing a second heteroatomselected from nitrogen, oxygen and sulphur, which heterocycle mayoptionally bear one or two oxo or thioxo substituents and up to foursubstituents having the meanings defined hereinbefore for furthersubstituents on Q; and A¹, X¹, Ar, R¹, R² and R³ have any of themeanings defined hereinbefore;

(b) Q is indolyl, indolinyl, benzimidazolyl, 2,3-dihydrobenzimidazolyl,1H-indazolyl, 2,3-dihydro-1H-indazolyl, benzoxazolyl,2,3-dihydrobenzoxazolyl, benzothiazolyl or 2,3-dihydrobenzothiazolyl,which may optionally bear one or two oxo or thioxo substituents and upto four substituents having the meanings defined hereinbefore forfurther substituents on Q; and A¹, X¹, Ar, R¹, R² and R³ have any of themeanings defined hereinbefore;

(c) Q is 2-indolyl, 3-indolyl, 5-indolyl, 6-indolyl, 2-benzimidazolyl,5-benzimidazolyl, 6-benzimidazolyl, 1H-indazol-5-yl, 1H-indazol-6-yl,2-benzoxazolyl, 5-benzoxazolyl, 6-benzoxazolyl, 2-benzothiazolyl,5-benzothiazolyl or 6-benzothiazolyl, which may optionally bear one ortwo substituents having the meanings defined hereinbefore for furthersubstituents on Q; and A¹, X¹, Ar, R¹, R² and R³ have any of themeanings defined hereinbefore;

(d) Q is 2-oxoindolinyl, 2,3-dioxoindolinyl,2-oxo-2,3-dihydrobenzimidazolyl, 3-oxo-2,3-dihydro-1H-indazolyl,2-oxo-2,3-dihydrobenzoxazolyl or 2-oxo-2,3-dihydrobenzothiazolyl, or thecorresponding thioxo derivatives thereof, which may optionally bear upto four substituents having the meanings defined hereinbefore forfurther subsituents on Q; and A¹, X¹, Ar, R¹, R² and R³ have any of themeanings defined hereinbefore;

(e) Q is 2-oxoindolin-3-yl, 2-oxoindolin-5-yl, 2-oxoindolin-6-yl,2,3-dioxoindolin-5-yl, 2,3-dioxoindolin-6-yl,2-oxo-2,3-dihydrobenzimidazol-5-yl, 2-oxo-2,3-dihydrobenzimidazol-6-yl,3-oxo-2,3-dihydro-1H-indazol-5-yl, 3-oxo-2,3-dihydro-1H-indazol-6-yl,2-oxo-2,3-dihydrobenzoxazol-5-yl, 2-oxo-2,3-dihydrobenzoxazol-6-yl,2-oxo-2,3-dihydrobenzothiazol-5-yl or2-oxo-2,3-dihydrobenzothiazol-6-yl, or the corresponding thioxoderivatives thereof, which may optionally bear up to four substituentshaving the meanings defined hereinbefore for further substituents on Q;and A¹, X¹, Ar, R¹, R² and R³ have any of the meanings definedhereinbefore;

(f) A¹ is a direct link to X¹, and X¹ is oxy, thio, sulphinyl orsulphonyl; and Q, Ar, R¹, R² and R³ have any of the meanings definedhereinbefore;

(g) A¹ is methylene and X¹ is oxy, thio, sulphinyl or sulphonyl; and Q,Ar, R¹, R² and R³ have any of the meanings defined hereinbefore;

(h) Ar is 1,3-phenylene or 1,4-phenylene which may optionally bear oneor two substituents selected from fluoro, chloro, hydroxy, amino, nitro,ureido, methyl, methoxy, methylamino, dimethylamino, trifluoromethyl andacetamido; and Q, A¹, X¹, R¹, R² and R³ have any of the meanings definedhereinbefore;

(i) Ar is 3,5-pyridylene; and Q, A¹, X¹, R¹, R² and R³ have any of themeanings defined hereinbefore;

(j) R¹ is methyl, ethyl, allyl or 2-propynyl; and Q, A¹, X¹, Ar, R² andR³ have any of the meanings defined hereinbefore;

(k) R² and R³ together form a group of the formula --A² --X² --A³ --which, together with the carbon atom to which A² and A³ are attached,defines a ring having 5 to 7 ring atoms, wherein A² and A³, which may bethe same or different, each is methylene, ethylene or trimethylene andX² is oxy, and which ring may bear one or two substituents selected fromhydroxy, methyl, ethyl, propyl, methoxy and ethoxy; and Q, A¹, X¹, Arand R¹ have any of the meanings defined hereinbefore; or

(l) R¹ and R² together form a group of the formula --A² --X² --A³ --which, together with the oxygen atom to which A² is attached and withthe carbon atom to which A³ is attached, defines a ring having 5 to 7ring atoms, wherein A² and A³, which may be the same or different, eachis methylene or ethylene and X² is oxy, and which ring may bear one, twoor three substituents selected from methyl, ethyl and propyl, and R³ ismethyl or ethyl; and Q, A¹, X¹ and Ar have any of the meanings definedhereinbefore;

or a pharmaceutically-acceptable salt thereof.

A preferred compound of the invention comprises a bicyclic heterocyclicderivative of the formula I

wherein Q is indolyl, indolinyl, benzimidazolyl,2,3-dihydrobenzimidazolyl, 1H-indazolyl, 2,3-dihydro-1H-indazolyl,benzoxazolyl, 2,3-dihydrobenzoxazolyl, benzothiazolyl or2,3-dihydrobenzothiazolyl, which may optionally bear one or two oxo orthioxo substituents and up to four substituents selected from fluoro,chloro, bromo, hydroxy, cyano, amino, methyl, ethyl, propyl, methoxy,trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluorethyl, 2-methylaminoethyl,2-dimethylaminoethyl, phenyl and benzyl, and

wherein said phenyl or benzyl substituent may optionally bear asubstituent selected from chloro, methyl and methoxy;

A¹ is a direct link to X¹ or is methylene;

X¹ is oxy, thio, sulphinyl or sulphonyl;

Ar is 1,3-phenylene or 1,4-phenylene which may optionally bear one ortwo substituents selected from fluoro, chloro, hydroxy, amino, nitro,ureido, methoxy, dimethylamino, trifluoromethyl and acetamido; or

Ar is 3,5-pyridylene;

R¹ is methyl, ethyl, allyl or 2-propynyl; and

R² and R³ together form a group of the formula --A² --X² --A³ -- which,together with the carbon atom to which A² and A³ are attached, defines aring having 5 or 6 ring atoms, wherein A² is ethylene, A³ is methyleneor ethylene, and X² is oxy, and which ring may bear one or twosubstituents selected from methyl, ethyl, propyl, methoxy and ethoxy;

or R¹ and R² together form a group of the formula --A² --X² --A³ --which, together with the oxygen atom to which A² is attached and withthe carbon atom to which A³ is attached, defines a ring having 5 or 6ring atoms, wherein A² is methylene, A³ is methylene or ethylene, and X²is oxy, and which ring may bear one, two or three substituents selectedfrom methyl, ethyl and propyl, and R³ is methyl or ethyl;

or a pharmaceutically-acceptable salt thereof.

A further preferred compound of the invention comprises a bicyclicheterocyclic derivative of the formula I

wherein Q is 2-oxoindolin-5-yl, 2,3-dioxoindolin-5-yl,2-oxo-2,3-dihydrobenzimidazol-5-yl, 2-oxo-2,3-dihydrobenzoxazol-6-yl or2-oxo-2,3-dihydrobenzothiazol-6-yl which may optionally bear one, two orthree substituents selected from fluoro, chloro, hydroxy, methyl, ethyl,propyl, 2-fluoroethyl, 2-dimethylaminoethyl, phenyl and benzyl;

A¹ is a direct link to X¹, or is methylene;

X¹ is oxy, thio, sulphinyl or sulphonyl;

Ar is 1,3-phenylene or 1,4-phenylene which may optionally bear one ortwo substituents selected from fluoro, hydroxy, amino, nitro, ureido,methoxy, dimethylamino, trifluoromethyl and acetamido; or

Ar is 3,5-pyridylene;

R¹ is methyl, ethyl, allyl or 2-propynyl; and

R² and R³ together form a group of the formula --A² --X² --A³ -- which,together with the carbon atom to which A² and A³ are attached, defines aring having 5 or 6 ring atoms, wherein A² is ethylene, A³ is methyleneor ethylene, and X² is oxy, and which ring may bear one or twosubstituents selected from methyl and ethyl;

or R¹ and R² together form a group of the formula --A² --X² --A³ --which, together with the oxygen atom to which A² is attached and withthe carbon atom to which A³ is attached, defines a ring having 5 ringatoms wherein A² is methylene, A³ is methylene, and X² is oxy, and whichring may bear one, two or three substituents selected from methyl andethyl, and R³ is methyl or ethyl;

or a pharmaceutically-acceptable salt thereof.

A further preferred compound of the invention comprises a bicyclicheterocylic derivative of the formula I

wherein Q is 2-oxoindolin-5-yl, 2-oxo-2,3-dihydrobenzimidazol-5-yl,2-oxo-2,3-dihydrobenzoxazol-6-yl or 2-oxo-2,3-dihydrobenzothiazol-6-yl,or the corresponding N-methyl or N-ethyl derivatives thereof, which mayoptionally bear one or two methyl substituents;

A¹ is a direct link to X¹, or is methylene;

X¹ is oxy or thio;

Ar is 1,3-phenylene which may optionally bear one or two substituentsselected from fluoro, methoxy and trifluoromethyl;

R¹ is methyl, ethyl or allyl; and

R² and R³ together form a group of the formula --A² --X² --A³ -- which,together with the carbon atom to which A² and A³ are attached, defines aring having 5 or 6 ring atoms wherein is ethylene, A³ is methylene orethylene and X² is oxy, and which ring may bear a substituent selectedfrom methyl, ethyl, propyl and methoxy;

or a pharmaceutically-acceptable salt thereof.

A further preferred compound of the invention comprises a bicyclicheterocyclic derivative of the formula I

wherein Q is 2-oxoindolin-5-yl, 2-oxo-2,3-dihydrobenzimidazol-5-yl,2-oxo-2,3-dihydrobenzoxazol-6-yl or 2-oxo-2,3-dihydrobenzothiazol-6-yl,or the corresponding N-methyl or N-ethyl derivatives thereof, which mayoptionally bear one or two substituents selected from fluoro, hydroxyand methyl;

A¹ is a direct link to X¹, or is methylene;

X¹ is oxy or thio;

Ar is 1,3-phenylene which may optionally bear one or two substituentsselected from fluoro, methoxy and trifluoromethyl;

R¹ is methyl, ethyl or allyl; and

R² and R³ together form a group of the formula --A² --X² --A³ -- which,together with the carbon atom to which A and are attached, defines aring having 5 or 6 ring atoms, wherein A² is ethylene, A³ is methyleneor ethylene and X² is oxy, and which ring may bear a substituentselected from methyl, ethyl, propyl and methoxy;

or a pharmaceutically-acceptable salt thereof.

An especially preferred compound of the invention comprises a bicyclicheterocyclic derivative of the formula I

wherein Q is 1,3,3-trimethyl-2-oxoindolin-5-yl,1,3-dimethyl-2-oxo-2,3-dihydrobenzimidazol-5-yl or3-methyl-2-oxo-2,3-dihydrobenzothiazol-6-yl;

A¹ is a direct link to X¹ ;

X¹ is thio;

Ar is 1,3-phenylene or 5-fluoro-1,3-phenylene;

R¹ is methyl; and

R² and R³ together form a group of the formula --A² --X² --A³ -- which,together with the carbon atom to which A² and A³ are attached, defines aring having 6 ring atoms, wherein each of A² and A³ is ethylene and

X² is oxy, and which ring may bear a methyl or ethyl substituent alphato X² ;

or a pharmaceutically-acceptable salt thereof.

A further especially preferred compound of the invention comprises abicyclic heterocyclic derivative of the formula I

wherein Q is 1,3,3-trimethyl-2-oxoindolin-5-yl,1,3-dimethyl-2-oxo-2,3-dihydrobenzimidazol-5-yl,3-methyl-2-oxo-2,3-dihydrobenzothiazol-6-yl or3,3-difluoro-1-methyl-2-oxoindolin-5-yl;

A¹ is a direct link to X¹ ;

X¹ is thio;

Ar is 1,3-phenylene or 5-fluoro-1,3-phenylene;

R¹ is methyl; and

R² and R³ together form a group of the formula --A² --X² --A³ -- which,together with the carbon atom to which A² and A³ are attached, defines aring having 6 ring atoms, wherein each of A² and A³ is ethylene and

X² is oxy, and which ring may bear a methyl or ethyl substituent alphato X² ;

or a pharmaceutically-acceptable salt thereof.

Specific especially preferred compounds of the invention include, forexample, the following bicyclic heterocyclic derivatives of the formulaI, or pharmaceutically-acceptable salts thereof:4-methoxy-4-[3-(1,3,3-trimethyl-2-oxoindolin-5-ylthio)phenyl]tetrahydropyran,4-[3-(1,3-dimethyl-2-oxo-2,3-dihydrobenzimidazol-5-ylthio)phenyl]-4-methoxytetrahydropyranand4-methoxy-4-[3-(3-methyl-2-oxo-2,3-dihydrobenzothiazol-6-ylthio)phenyl]tetrahydropyran.

Further specific especially preferred compounds of the inventioninclude, for example, the following bicyclic heterocyclic derivatives ofthe formula I, or pharmaceutically-acceptable salts thereof:4-[5-fluoro-3-(3-methyl-2-oxo-2,3-dihydrobenzothiazol-6-ylmethoxy)phenyl]-4-methoxytetrahydropyran,4-[5-fluoro-3-(1,3-dimethyl-2-oxo-2,3-dihydrobenzimidazol-5-ylmethoxy)phenyl]-4-methoxytetrahydropyranand4-[5-fluoro-3-(3,3-difluoro-1-methyl-2-oxoindolin-5-ylmethoxy)phenyl]-4-methoxytetrahydropyran.

A compound of the invention comprising a bicyclic heterocyclicderivative of the formula I, or a pharmaceutically-acceptable saltthereof, may be prepared by any process known to be applicable to thepreparation of structurally-related compounds. Such procedures areprovided as a further feature of the invention and are illustrated bythe following representative examples in which, unless otherwise statedQ, A¹, X¹, Ar, R¹, R² and R³ have any of the meanings definedhereinbefore.

(a) The coupling, preferably in the presence of a suitable base, of acompound of the formula Q--A¹ --X¹ --H with a compound of the formula IIwherein Z is a displaceable group; provided that, when there is anamino, alkylamino or hydroxy group in Q, Ar, R² or R³, any amino,alkylamino or hydroxy group may be protected by a conventionalprotecting group or alternatively any such group need not be protected,whereafter any undesired protecting group in Q, Ar, R² or R³ is removedby conventional means.

A suitable displaceable group Z is, for example, a halogeno orsulphonyloxy group, for example a chloro, bromo, iodo,methanesulphonyloxy or toluene-p-sulphonyloxy group.

A suitable base for the coupling reaction is, for example, an alkali oralkaline earth metal carbonate, (1-4C)alkoxide, hydroxide or hydride,for example sodium carbonate, potassium carbonate, sodium ethoxide,sodium butoxide, sodium hydroxide, potassium hydroxide, sodium hydrideor potassium hydride. The coupling reaction is conveniently performed ina suitable inert solvent or diluent, for example N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethylsulphoxide,acetone, 1,2-dimethoxyethane or tetrahydrofuran, and at a temperature inthe range, for example, 10° to 150° C., conveniently at or near 100° C.

Conveniently the reaction may be performed in the presence of a suitablecatalyst, for example a metallic catalyst, for example palladium(O) orcopper(I) such as tetrakis(triphenylphosphine)palladium, cuprouschloride or cuprous bromide.

A suitable protecting group for an amino or alkylamino group is, forexample, an acyl group for example a (2-4C)alkanoyl group (especiallyacetyl), a (1-4C)alkoxycarbonyl group (especially methoxycarbonyl,ethoxycarbonyl or tert-butoxycarbonyl), an arylmethoxycarbonyl group(especially benzyloxycarbonyl) or an aroyl group (especially benzoyl).The deprotection conditions for the above protecting groups necessarilyvary with the choice of protecting group. Thus, for example, an acylgroup such as ah alkanoyl or alkoxycarbonyl or an aroyl group may beremoved for example, by hydrolysis with a suitable base such as analkali metal hydroxide, for example lithium or sodium hydroxide.Alternatively an acyl group such as a tert-butoxycarbonyl group may beremoved, for example, by treatment with a suitable acid such ashydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid andan arylmethoxycarbonyl group such as a benzyloxycarbonyl group may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-charcoal.

A suitable protecting group for a hydroxy group is, for example, an acylgroup, for example a (2-4C)alkanoyl group (especially acetyl), an aroylgroup (especially benzoyl) or an arylmethyl group (especially benzyl).The deprotection conditions for the above protecting groups willnecessarily vary with the choice of protecting group. Thus, for example,an acyl group such as an alkanoyl or an aroyl group may be removed, forexample, by hydrolysis with a suitable base such as an alkali metalhydroxide, for example lithium or sodium hydroxide. Alternatively anarylmethyl group such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-charcoal.

The starting materials of the formula Q--A¹ --X¹ --H and of the formulaII may be obtained by standard procedures of organic chemistry. Thus,for example, when a starting material of the formula Q-SH is required,it may be obtained by, for example, the reaction of a heterocyclicmoiety of the formula Q-H as defined hereinbefore with ahalosulphonylating agent such as, for example, chlorosulphonic acid, ina suitable solvent or diluent, for example dichloroethane or pyridine,and at a temperature in the range, for example 40° to 150° C.,conveniently at or near 100° C. The intermediate of, for example, theformula Q--SO₂ --Cl so produced may be reduced to a compound of theformula Q--SH by a conventional reducing agent such as, for example, asuitable reducing metallic salt such as a metallic halide, for example astannous halide, conveniently stannous chloride, in a suitable solventor diluent such as a (2-4C)alkanoic acid, for example acetic acid, andat a temperature in the range, for example, 40° to 150° C., convenientlyin the range 80° to 100° C. Alternatively the reducing agent may be asuitable reducing metal, such as zinc or iron, in the presence of astrong acid, such as hydrochloric, sulphuric or phosphoric acid, and ata temperature in the range, for example 10° to 150° C., conveniently ator near 100° C.

Conveniently intermediates of the formula II wherein Z, Ar, R¹, R² andR³ have the meanings defined hereinbefore may be obtained by way ofcompounds of the formula Z--Ar--Y, wherein Z and Ar have the meaningsdefined hereinbefore and Y is, for example, a halogeno, formyl,alkanoyl, nitrile or alkoxycarbonyl group, as illustrated inaccompanying Scheme I (set out hereinafter). Thus, for example, in theaccompanying non-limiting Examples it is shown how to convert a compoundof the formula Z--Ar--Y wherein Y is a halogeno group to a compound ofthe formula II.

It will also be appreciated that the intermediate of the formula II mayconveniently be obtained from the compound of the formula Z--Ar--Y, asdefined hereinbefore, by reversing the order of introduction of thegroups R² and R³ which is used in Scheme I.

(b) The coupling, preferably in the presence of a suitable base asdefined hereinbefore, of a compound of the formula III with a compoundof the formula Q--A¹ --Z wherein Z is a displaceable group as definedhereinbefore; provided that, when there is an amino, alkylamino orhydroxy group in Q, Ar, R² or R³, any amino, alkylamino or hydroxy groupmay be protected by a conventional protecting group as definedhereinbefore or alternatively any such group need not be protected,whereafter any undesired protecting group in Q, Ar, R² or R³ is removedby conventional means.

The coupling reaction is conveniently performed in a suitable inertsolvent as defined hereinbefore and at a temperature in the range, forexample, 10° to 150° C., conveniently at or near 100° C. The reactionmay conveniently be performed in the presence of a suitable catalyst asdefined hereinbefore.

The starting materials of the formula Q--A¹ --Z and of the formula Illmay be obtained by standard procedures of organic chemistry. Thepreparation of such starting materials is described within theaccompanying non-limiting Examples which are provided for the purpose ofillustration only. Alternatively necessary starting materials areobtainable by analogous procedures to those illustrated in accompanyingScheme II (set out hereinafter) or by modifications thereto which arewithin the ordinary skill of an organic chemist.

A suitable protecting group R⁴, as employed in Scheme II, is any one ofthe many such groups known in the art and includes any appropriateprotecting group as defined hereinbefore. Examples of such groups aregiven in Scheme II. The conditions for the introduction and removal ofsuch protecting groups are described in standard textbooks of organicchemistry such as, for example, "Protective Groups in Organic Synthesis"by T. W. Green (J Wiley and Sons, 1981).

(c) The alkylation, preferably in the presence of a suitable base asdefined hereinbefore, of a compound of the formula IV with a compound ofthe formula R¹ --Z wherein R¹ and Z have the meanings definedhereinbefore; provided that, when there is an amino, imino, alkylaminoor hydroxy group in Q, X¹, Ar, R² R³ any amino, imino, alkylamino orhydroxy group may be protected by a conventional protecting group oralternatively any such group need not be protected, whereafter anyundesired protecting group in Q, X¹, Ar, R² or R³ is removed byconventional means.

A suitable protecting group for an imino group is, for example, any ofthe protecting groups defined hereinbefore for an amino or alkylaminogroup.

The tertiary alcohol starting material of the formula IV may be obtainedby standard procedures of organic chemistry. Conveniently, and asillustrated in accompanying Scheme III (set out hereinafter),intermediates of the formulae Q--A¹ --X¹ --Ar--Y, wherein Q, A¹ X¹ andAr have the meanings defined hereinbefore and Y is, for example, ahalogeno, formyl, alkanoyl, nitrile or alkoxycarbonyl group may beutilised in the preparation of the tertiary alcohol starting material ofthe formula IV.

(d) For the production of those compounds of the formula I wherein R¹and R² together form a group of the formula --A² --X² --A³ -- which,together with the oxygen atom to which A² is attached, defines a ringhaving 5 to 7 ring atoms and wherein A², X² and A³ have the meaningsdefined hereinbefore, and wherein R³ has the meaning definedhereinbefore; the cyclisation of a compound of the formula V uponreaction with an appropriate aldehyde or ketone, or with a hemiacetal oracetal thereof, or with a compound of the formula Z--A² --Z, wherein Zhas the meaning defined hereinbefore; provided that, when there is anamino, imino, alkylamino or hydroxy group in Q, X¹ or Ar, any amino,imino, alkylamino or hydroxy group is protected by a conventionalprotecting group, whereafter any undesired protecting group in Q, X¹ orAr is removed by conventional means.

The cyclisation of a compound of the formula V with an appropriatealdehyde or ketone, or with a hemiacetal or acetal thereof, isconveniently carried out in the presence of a suitable acid. A suitableacid for the cyclisation reaction is, for example, an inorganic acidsuch as hydrochloric, sulphuric or phosphoric acid, or, for example, anorganic acid such as p-toluenesulphonic acid or trifluoroacetic acid.The cyclisation reaction is conveniently performed in a suitable inertsolvent or diluent, for example 1,2-dimethoxyethane or tetrahydrofuran.Preferably the reaction is performed using the appropriate aldehyde orketone, or a hemiacetal or acetal derivative thereof, as both a reactantand diluent. The cyclisation is effected at a temperature in the range;for example, 20° to 150° C., conveniently at or near the boiling pointof the diluent or solvent.

The cyclisation of a compound of the formula V with a compound of theformula Z--A² --Z is conveniently carried out in the presence of asuitable base as defined hereinbefore.

The tertiary alcohol starting material of the formula V may be obtainedby standard procedures of organic chemistry. Conveniently, and asillustrated in accompanying Scheme IV (set out hereinafter),intermediates of the formula Q--A¹ --X¹ --Ar--Y, wherein Q, A¹, X¹, Arand Y have the meanings defined hereinbefore, may be utilised in thepreparation of the tertiary alcohol starting material of the formula V.

A suitable protecting group R⁴, as defined hereinbefore, is employed.

(e) For the production of those compounds of the formula I wherein X¹ isa sulphinyl or sulphonyl group, wherein R² and R³ together form a groupof the formula --A² --X² --A³ -- and X² is a sulphinyl or sulphonylgroup or wherein R¹ and R² together form a group of the formula --A²--X² --A³ -- and X² is a sulphinyl or sulphonyl group, the oxidation ofa compound of the formula I wherein X is a thio group, wherein R² and R³together form a group of the formula --A² --X² --A³ -- and X² is a thiogroup or wherein R¹ and R² together form a group of the formula --A²--X² --A³ -- and X² is a thio group.

A suitable oxidising agent is, for example, any agent known in the artfor the oxidation of thio to sulphinyl and/or sulphonyl, for example,hydrogen peroxide, a peracid (such as 3-chloroperoxybenzoic orperoxyacetic acid), an alkali metal peroxysulphate (such as potassiumperoxymonosulphate), chromium trioxide or gaseous oxygen in the presenceof platinum. The oxidation is generally carried out under as mildconditions as possible and with the required stoichiometric amount ofoxidising agent in order to reduce the risk of over oxidation and damageto other functional groups. In general the reaction is carried out in asuitable solvent or diluent such as methylene chloride, chloroform,acetone, tetrahydrofuran or tert-butyl methyl ether and at atemperature, for example, at or near ambient temperature, that is in therange 15° to 35° C. When a compound carrying a sulphinyl group isrequired a milder oxidising agent may also be used, for example sodiumor potassium metaperiodate, conveniently in a polar solvent such asacetic acid or ethanol. It will be appreciated that when a compound ofthe formula I containing a sulphonyl group is required, it may beobtained by oxidation of the corresponding sulphinyl compound as well asof the corresponding thio compound.

(f) For the production of those compounds of the formula I wherein Arbears an alkanoylamino substituent, the acylation of a compound of theformula I wherein Ar bears an amino substituent.

A suitable acylating agent is, for example, any agent known in the artfor the acylation of amino to acylamino, for example an acyl halide, forexample a (2-6C)alkanoyl chloride or bromide, in the presence of asuitable base, an alkanoic acid anhydride, for example a (2-6C)alkanoicacid anhydride, or an alkanoic acid mixed anhydride, for example themixed anhydride formed by the reaction of an alkanoic acid and a(1-4C)alkoxycarbonyl halide, for example a (1-4C)alkoxycarbonylchloride, in the presence of a suitable base. In general the reaction iscarried out in a suitable solvent or diluent such as methylene chloride,acetone, tetrahydrofuran or tert-butyl methyl ether and at atemperature, for example, at or near ambient temperature, that is in therange 15° to 35° C. A suitable base when it is required is, for example,pyridine, 4-dimethylaminopyridine, triethylamine, ethyldiisopropylamine,N-methylmorpholine, an alkali metal carbonate, for example potassiumcarbonate, or an alkali metal carboxylate, for example sodium acetate.

(g) For the production of those compounds of the formula I wherein Qbears an alkyl or substituted alkyl substituent on an available nitrogenatom, or wherein Ar bears an alkoxy substituent, the alkylation of acompound of the formula I wherein Q bears a hydrogen atom on saidavailable nitrogen atom, or wherein Ar bears a hydroxy substituent.

A suitable alkylating agent is, for example, any agent known in the artfor the alkylation of an available nitrogen atom, or of hydroxy toalkoxy, for example an alkyl or substituted alkyl halide, for example a(1-6C)alkyl chloride, bromide or iodide or a substituted (1-4C)alkylchloride, bromide or iodide, in the presence of a suitable base. Asuitable base for the alkylation reaction is, for example, an alkali oralkaline earth metal carbonate, sodium hydroxide, potassium hydroxide,sodium hydride or potassium hydride. The alkylation reaction ispreferably performed in a suitable inert solvent of diluent, for exampleN,N-dimethylformamide, dimethylsulphoxide, acetone, 1,2-dimethoxyethaneor tetrahydrofuran, and at a temperature in the range, for example, 10°to 150° C., conveniently at or near ambient temperature.

When a pharmaceutically-acceptable salt of a novel compound of theformula I is required, it may be obtained, for example, by reaction ofsaid compound with a suitable acid or base using a conventionalprocedure. When an optically active form of a compound of the formula Iis required, it may be obtained by carrying out one of the aforesaidprocedures using an optically active starting material, or by resolutionof a racemic form of said compound using a conventional procedure.

Many of the intermediates defined herein are novel, for example those ofthe formulae IV and V and these are provided as a further feature of theinvention.

As stated previously, the novel compounds of the formula I areinhibitors of the enzyme 5-LO. The effects of this inhibition may bedemonstrated using one or more of the standard procedures set out below:

a) An in vitro spectrophotometric enzyme assay system, which assessesthe inhibitory properties of a test compound in a cell free system using5-LO isolated from guinea pig neutrophils and as described by D. Aharonyand R. L. Stein (J. Biol. Chem., 1986, 261(25), 11512-11519). This testprovides a measure of the intrinsic inhibitory properties of a testcompound against soluble 5-LO in an extracellular environment.

b) An in vitro assay system involving incubating a test compound withheparinised human blood, prior to challenge with the calcium ionophoreA23187 and then indirectly measuring the inhibitory effects on 5-LO byassaying the amount of LTB₄ using specific radioimmunoassays describedby Carey and Forder (F. Carey and R. A. Forder, Prostaglandins,Leukotrienes Med., 1986, 22, 57; Prostaglandins, 1984, 28, 666; Brit. J.Pharmacol. 1985, 84, 34P) which involve the use of a protein-LTB₄conjugate produced using the procedure of Young et alia (Prostaglandins,1983, 26(4), 605-613). The effects of a test compound on the enzymecyclooxygenase (which is involved in the alternative metabolic pathwayfor arachidonic acid and gives rise to prostaglandins, thromboxanes andrelated metabolites) may be measured at the same time using the specificradioimmunoassay for thromboxane B₂ (TxB₂) described by Carey and Forder(see above). This test provides an indication of the effects of a testcompound against 5-LO and also cyclooxygenase in the presence of bloodcells and proteins. It permits the selectivity of the inhibitory effecton 5-LO or cyclooxygenase to be assessed.

c) An ex vivo assay system, which is a variation of test b) above,involving administration of a test compound (usually orally as thesuspension produced when a solution of the test compound indimethylsulphoxide is added to carboxymethylcellulose), bloodcollection, heparinisation, challenge with A23187 and radioimmunoassayof LTB₄ and TxB₂. This test provides an indication of thebioavailability of a test compound as an inhibitor of 5-LO orcyclooxygenase.

d) An in vitro assay system involving the measurement of the inhibitoryproperties of a test compound against the liberation of LTC₄ and PGE₂induced by zymosan on mouse resident peritoneal macrophages, using theprocedure of Humes (J. L. Humes et alia, Biochem. Pharmacol., 1983, 32,2319-2322) and conventional radioimmunoassay systems to measure LTC₄ andPGE₂. This test provides an indication of inhibitory effects against5-LO and cyclooxygenase in a non-proteinaceous system.

e) An in vivo system involving the measurement of the effects of a testcompound in inhibiting the inflammatory response to arachidonic acid inthe rabbit skin model developed by D. Aked et alia (Brit. J. Pharmacol.,1986, 89, 431-438). This test provides an in vivo model for 5-LOinhibitors administered topically or orally.

f) An in vivo system involving measuring the effects of a test compoundadministered orally or intravenously on a leukotriene dependentbronchoconstriction induced by an antigen challenge in guinea pigspre-dosed with an antihistamine (mepyramine), a β-adrenergic blockingagent (propranolol) and a cyclooxygenase inhibitor (indomethacin), usingthe procedure of W. H. Anderson et alia (British J. Pharmacology, 1983,78(1), 67-574). This test provides a further in vivo test for detecting5-LO inhibitors.

g) An in vivo system involving measuring the effects of a test compoundadministered orally against the liberation of LTB₄ induced by zymosanwithin an air pouch generated within the subcutaneous tissue of the backof male rats. The rats are anaesthetised and air pouches are formed bythe injection of sterile air (20 ml). A further injection of air (10 ml)is similarly given after 3 days. At 6 days after the initial airinjection the test compound is administered (usually orally as thesuspension produced when a solution of the test compound indimethylsulphoxide is added to hydroxypropylmethylcellulose), followedby the intrapouch injection of zymosan (1 ml of a 1% suspension inphysiological saline). After 3 hours the rats are killed, the airpouches are layaged with physiological saline, and the specificradioimmunoassay described above is used to assay LTB₄ in the washings.This test provides an indication of inhibitory effects against 5-LO inan inflammatory milieu.

Although the pharmacological properties of the compounds of the formulaI vary with structural changes as expected, in general compounds of theformula I possess 5-LO inhibitory effects at the followingconcentrations or doses in one or more of the above tests a)-f):

Test a): IC₅₀ in the range, for example, 0.01-30 μM;

Test b): IC₅₀ (LTB₄) in the range, for example, 0.01-40 μM

IC₅₀ (TxB₂) in the range, for example, 40-200 μM;

Test c): oral ED₅₀ (LTB₄) in the range, for example, 1-100 mg/kg;

Test d): IC₅₀ (LTC₄) in the range, for example, 0.001-1 μM,

IC₅₀ (PGE₂) in the range, for example, 20-1000 μM;

Test e): inhibition of inflammation in the range, for example, 0.3-100μg intradermally;

Test f): ED₅₀ in the range, for example, 0.5-10 mg/kg i.v.;

Test g): oral ED₅₀ (LTB₄) in the range, for example, 0.5-50mg/kg.

No overt toxicity or other untoward effects are present in tests c), e),f) and/or g) when compounds of the formula I are administered at severalmultiples of their minimum inhibitory dose or concentration. Thus, byway of example, the compound4-[3-(1,3-dimethyl-2-oxo-2,3-dihydrobenzimidazol-5-ylthio)phenyl]-4-methoxytetrahydropyranhas an IC₅₀ of 0.05 μM against LTB₄ in test b), and an oral ED₅₀ of <2mg/kg versus LTB₄ in test g). In general those compounds of the formulaI which are particularly preferred have an IC₅₀ of <1 μM against LTB₄ intest b), and an oral ED₅₀ of <100 mg/kg against LTB₄ in tests c) and/org).

These compounds are examples of compounds of the invention which showselective inhibitory properties for 5-LO as opposed to cyclooxygenase,which selective properties are expected to impart improved therapeuticproperties, for example, a reduction in or freedom from thegastrointestinal side-effects frequently associated with cyclooxygenaseinhibitors such as indomethacin.

According to a further feature of the invention there is provided apharmaceutical composition which comprises a bicyclic heterocyclicderivative of the formula I, or a pharmaceutically-acceptable saltthereof, in association with a pharmaceutically-acceptable diluent orcarrier.

The composition may be in a form suitable for oral use, for example atablet, capsule, aqueous or oily solution, suspension or emulsion; fortopical use, for example a cream, ointment, gel or aqueous or oilysolution or suspension; for nasal use, for example a snuff, nasal sprayor nasal drops; for vaginal or rectal use, for example a suppository;for administration by inhalation, for example as a finely divided powderor a liquid aerosol; for sub-lingual or buccal use, for example a tabletor capsule; or for parenteral use (including intravenous, subcutaneous,intramuscular, intravascular or infusion), for example a sterile aqueousor oily solution or suspension. In general the above compositions may beprepared in a conventional manner using conventional excipients.

The amount of active ingredient (that is a bicyclic heterocyclicderivative of the formula I, or a pharmaceutically-acceptable saltthereof) that is combined with one or more excipients to produce asingle dosage form will necessarily vary depending upon the host treatedand the particular route of administration. For example, a formulationintended for oral administration to humans will generally contain, forexample, from 0.5 mg to 2 g of active agent compounded with anappropriate and convenient amount of excipients which may vary fromabout 5 to about 98 percent by weight of the total composition. Dosageunit forms will generally contain about 1 mg to about 500 mg of anactive ingredient.

According to a further feature of the invention there is provided abicyclic heterocyclic derivative of the formula I, or apharmaceutically-acceptable salt thereof, for use in a method oftreatment of the human or animal body by therapy.

The invention also includes a method of treating a disease or medicalcondition mediated alone or in part by one or more leukotrienes whichcomprises administering to a warm-blooded animal requiring suchtreatment an effective amount of an active ingredient as defined above.The invention also provides the use of such an active ingredient in theproduction of a new medicament for use in a leukotriene mediated diseaseor medical condition.

The size of the dose for therapeutic or prophylactic purposes of acompound of the formula I will naturally vary according to the natureand severity of the conditions, the age and sex of the animal or patientand the route of administration, according to well known principles ofmedicine. As mentioned above, compounds of the formula I are useful intreating those allergic and inflammatory conditions which are due aloneor in part to the effects of the metabolites of arachidonic acid arisingby the linear (5-LO catalysed) pathway and in particular theleukotrienes, the production of which is mediated by 5-LO. As previouslymentioned, such conditions include, for example, asthmatic conditions,allergic reactions, allergic rhinitis, allergic shock, psoriasis, atopicdermatitis, cardiovascular and cerebrovascular disorders of aninflammatory nature, arthritic and inflammatory joint disease, andinflammatory bowel diseases.

In using a compound of the formula I for therapeutic or prophylacticpurposes it will generally be administered so that a daily dose in therange, for example, 0.5 mg to 75 mg per kg body weight is received,given if required in divided doses. In general lower doses will beadministered when a parenteral route is employed. Thus, for example, forintravenous administration, a dose in the range, for example, 0.5 mg to30 mg per kg body weight will generally be used. Similarly, foradministration by inhalation, a dose in the range, for example, 0.5 mgto 25 mg per kg body weight will be used.

Although the compounds of the formula I are primarily of value astherapeutic agents for use in warm-blooded animals (including man), theyare also useful whenever it is required to inhibit the enzyme 5-LO.Thus, they are useful as pharmacological standards for use in thedevelopment of new biological tests and in the search for newpharmacological agents.

By virtue of their effects on leukotriene production, the compounds ofthe formula I have certain cytoprotective effects, for example they areuseful in reducing or suppressing certain of the adversegastrointestinal effects of the cyclooxygenase inhibitory non-steroidalanti-inflammatory agents (NSAIA), such as indomethacin, acetylsalicylicacid, ibuprofen, sulindac, tolmetin and piroxicam. Furthermore,co-administration of a 5-LO inhibitor of the Formula I with a NSAIA canresult in a reduction in the quantity of the latter agent needed toproduce a therapeutic effect, thereby reducing the likelihood of adverseside-effects. According to a further feature of the invention there isprovided a pharmaceutical composition which comprises a bicyclicheterocyclic derivative of the formula I, or apharmaceutically-acceptable salt thereof as defined hereinbefore, inconjunction or admixture with a cyclooxygenase inhibitory non-steroidalanti-inflammatory agent (such as mentioned above), and apharmaceutically-acceptable diluent or carrier.

The cytoprotective effects of the compounds of the formula I may bedemonstrated, for example in a standard laboratory model which assessesprotection against indomethacin-induced or ethanol-induced ulceration inthe gastrointestinal tract of rats.

The compositions of the invention may in addition contain one or moretherapeutic or prophylactic agents known to be of value for the diseaseunder treatment. Thus, for example a known platelet aggregationinhibitor, hypolipidemic agent, anti-hypertensive agent, beta-adrenergicblocker or a vasodilator may usefully also be present in apharmaceutical composition of the invention for use in treating a heartor vascular disease or condition. Similarly, by way of example, ananti-histamine, steroid (such as beclomethasone dipropionate), sodiumcromoglycate, phosphodiesterase inhibitor or a beta-adrenergic stimulantmay usefully also be present in a pharmaceutical composition of theinvention for use in treating a pulmonary disease or condition.

The invention will now be illustrated in the following non-limitingExamples in which, unless otherwise stated:

(i) evaporations were carried out by rotary evaporation in vacuo andwork-up procedures were carried out after removal of residual solids byfiltration;

(ii) operations were carried out at room temperature, that is in therange 18°-25° and under an atmosphere of an inert gas such as argon;

(iii) column chromatography (by the flash procedure) and medium pressureliquid chromatography (MPLC) were performed on Merck Kieselgel silica(Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) reversed-phase silicaobtained from E. Meck, Darmstadt, W. Germany;

(iv) yields are given for illustration only and are not necessarily themaximum attainable;

(v) the end-products of the formula I have satisfactory microanalysesand their structures were confirmed by NMR and mass spectral techniques;

(vi) intermediates were not generally fully characterised and purity wasassessed by thin layer chromatographic, infra-red (IR) or NMR analysis;

(vii) melting points are uncorrected and were determined using a MettlerSP62 automatic melting point apparatus or an oil-bath apparatus; meltingpoints for the end-products of the formula I were determined afterrecrystallisation from a conventional organic solvent such as ethanol,methanol, acetone, ether or hexane, alone or in admixture; and

(viii) the following abbreviations have been used:

    ______________________________________                                        THF             tetrahydrofuran;                                              DMSO            dimethylsulphoxide;                                           DMF             N,N-dimethylformamide;                                        DMA             N,N-dimethylacetamide.                                        ______________________________________                                    

EXAMPLE 1

A mixture of 5-iodo-1,3-dimethyl-2,3-dihydrobenzimidazol-2-one (0.44 g),4-(3-mercaptophenyl)-4-methoxytetrahydropyran (0.34 g), cuprous chloride(0.05 g), potassium carbonate (0.34 g) and DMF (1 ml) was stirredvigorously and heated to 140° C. for 1.5 hours. The mixture was cooledto ambient temperature and partitioned between water and ethyl acetate.The organic phase was washed with water, dried (MgSO₄) and evaporated.The residue was purified by column chromatography using ethyl acetate aseluent. There was thus obtained4-[3-(1,3-dimethyl-2-oxo-2,3-dihydrobenzimidazol-5-ylthio)phenyl]-4-methoxytetrahydropyran(0.285 g, 49%), m.p. 112° C.

NMR Spectrum (CDCl₃, δ values) 1.8-2.0 (m, 4H), 2.95 (s, 3H), 3.35 (s,3H), 3.45 (s, 3H), 3.75-3.90 (m, 4H), 6.9-7.3 (m, 7H).

The 5-iodo-1, 3-dimethyl-2,3-dihydrobenzimidazol-2-one used as astarting material was obtained as follows:

A mixture of 1,1'-carbonyldiimidazole (10.7 g) and THF (100 ml) wasadded to a mixture of 1,2-phenylenediamine (6.48 g) and THF (150 ml)which had been cooled to approximately 5° C. in an ice-water bath. Themixture was stirred at ambient temperature for 16 hours. The precipitatewas filtered off giving 2,3-dihydrobenzimidazol-2-one (4.38 g, 55%),m.p. >290° C.

Sodium hydride (55% w/w dispersion in oil, 2.8 g) was added portionwiseto a solution of 2,3-dihydrobenzimidazol-2-one (4.3 g) in DMF (100 ml)which had been cooled in an ice-water bath. The mixture was stirred atambient temperature for 1.5 hours, during which period a further portionof DMF (50 ml) was added to aid the stirring of the reaction mixture.Methyl iodide (5 ml) was added and the mixture was stirred at ambienttemperature for 16 hours. The mixture was evaporated and the residue waspartitioned between ethyl acetate and water. The organic phase waswashed with water and with brine, dried (MgSO₄) and evaporated. Theresidue was purified by column chromatography using a 2:1 v/v mixture oftoluene and ethyl acetate as eluent. There was thus obtained1,3-dimethyl-2,3-dihydrobenzimidazol-2-one (3.14 g, 60%), m.p. 104°-106°C.

A mixture of the product so obtained (0.5 g), iodine monochloride (0.5g) and glacial acetic acid (5 ml) was heated to 80° C. for 1 hour. Themixture was partitioned between a saturated aqueous sodium sulphitesolution and methylene chloride. The organic phase was washed with asaturated aqueous sodium bicarbonate solution, dried (MgSO₄) andevaporated. The residue was recrystallised from ethyl acetate. There wasthus obtained 5-iodo-1,3-dimethyl-2,3-dihydrobenzimidazol-2-one (0.36 g,41%), m.p. 142°-144° C.

The 4-(3-mercaptophenyl)-4-methoxytetrahydropyran used as a startingmaterial was obtained as follows:

A solution of 1,3-dibromobenzene (23.8 g) in THF (120 ml) was cooled to-78° C. and n-butyl-lithium (1.6M in hexane, 62.5 ml) was addeddropwise. The mixture was stirred at -78° C. for 30 minutes and asolution of tetrahydropyran-4-one (10 g) in THF (40 ml) was added. Theresultant suspension was stirred at -78° C. for 1 hour, allowed to warmto ambient temperature and then stirred for 30 minutes. The mixture waspoured into brine (250 ml) and extracted with diethyl ether. The organicphase was dried (MgSO₄) and evaporated. The residue was triturated underhexane and the resultant solid (16.8 g) was filtered off.

A solution of the product so obtained in DMF (100 ml) was added dropwiseto a slurry of sodium hydride (60% w/w dispersion in mineral oil; 5.25g) in DMF (10 ml) and the mixture was stirred at ambient temperature for90 minutes. Methyl iodide (36.5 g) was added and the mixture was stirredat ambient temperature for 16 hours. Ethanol (2 ml) and water (500 ml)was added in turn and the mixture was extracted with diethyl ether(3×200 ml). The combined extracts were washed with water, dried (MgSO₄)and evaporated. The residue was purified by column chromatography usingincreasingly polar mixtures of hexane and ethyl acetate as eluent. Therewas thus obtained 4-(3-bromophenyl)-4-methoxytetrahydropyran (12 g, 44%)as a gum. NMR Spectrum (CDCl₃, δ values) 1.88-2.1 (m, 4H), 3.0 (s, 3H),3.78-3.95 (m, 4H), 7.2-7.35 (m, 2H), 7.42 (m, 1 H), 7.55 (m, 1H).

A solution of 4-(3-bromophenyl)-4-methoxytetrahydropyran (1 g) in THF (4ml) was cooled to -80° C. under an atmosphere of argon andn-butyl-lithium (1.6M in hexane 2.4 , ml) was added dropwise. Themixture was stirred at -80° C. for 30 minutes, sulphur (0.12 g) wasadded and the mixture was stirred at -80° C. for a further 30 minutes.Water (10 ml) was added and the mixture was allowed to warm to ambienttemperature. The mixture was extracted with diethyl ether (10 ml). Theaqueous phase was acidified to pH4 by the addition of dilute aqueoushydrochloric acid solution and extracted with diethyl ether (2×10 ml).The combined organic extracts were dried (MgSO₄) and evaporated. Therewas thus obtained the required starting material as an oil (0.5 g) whichcrystallised on standing and was used without further purification.

EXAMPLE 2

The procedure described in Example 1 was repeated except that6-iodo-3-methyl-2,3-dihydrobenzothiazol-2-one was used in place of5-iodo-1,3-dimethyl-2,3-dihydrobenzimidazol-2-one. There was thusobtained4-methoxy-4-[3-(3-methyl-2-oxo-2,3-dihydrobenzothiazol-6-ylthio)phenyl]tetrahydropyranin 69% yield, m.p. 113°-114° C.

NMR Spectrum (CDCl₃, δ values) 1.85-2.05 (m, 4H), 3.0 (s, 3H), 3.45 (s,3H), 3.75-3.9 (m, 4H), 7.0-7.5 .(m, 7H).

The 6-iodo-3-methyl-2,3-dihydrobenzothiazol-2-one used as a startingmaterial was obtained as follows:

The procedures described in the portion of Example 1 which are concernedwith the preparation of5-iodo-1,3-dimethyl-2,3-dihydrobenzimidazol-2-one were repeated exceptthat 2-aminophenylthiol was used in place of 1,2-phenylenediamine. Therewere thus obtained in turn: 2,3-dihydrobenzothiazol-2-one in 55% yield,m.p. 133°-134° C.; 3-methyl-2,3-dihydrobenzothiazol-2-one in 77% yield,m.p. 74°-75° C.; and 6-iodo-3-methyl-2,3-dihydrobenzothiazol-2-one in37% yield, m.p. 130°-131° C.

EXAMPLE 3

The procedure described in Example 1 was repeated except that6-iodo-3-methyl-2,3-dihydrobenzoxazol-2-one was used in place of5-iodo-1,3-dimethyl-2,3-dihydrobenzimidazol-2-one. There was thusobtained4-methoxy-4-[3-(3-methyl-2-oxo-2,3-dihydrobenzoxazol-6-ylthio)phenyl]tetrahydropyranin 71% yield, m.p. 90°-92° C.

NMR Spectrum (CDCl₃, δ values) 1.85-2.05 (m, 4H), 2.95 (s, 3H), 3.4 (s,3H), 3.75-3.90 (m, 4H), 6.9-7.35 (m, 7H)

The 6-iodo-3-methyl-2,3-dihydrobenzoxazol-2-one used as a startingmaterial was obtained as follows:

A mixture of 1,1-carbonyldiimidazole (14.6 g), 2-aminophenol (6.54 g)and THF (200 ml) was heated to reflux for 2 hours. The mixture wasevaporated and the residue was partitioned between ethyl acetate andwater. The organic phase was washed with 2N aqueous hydrochloric acid,water and brine, dried (MgSO₄) and evaporated. The residue was purifiedby column chromatography using a 2:1 v/v mixture of toluene and ethylacetate as eluent. There was thus obtained 2,3-dihydrobenzoxazol-2-one(6.96 g, 86%), m.p. 136°-138° C.

The procedures described in the portion of Example 1 which are concernedwith the preparation of 5-iodo-1,3-dimethyl-2,3-dihydrobenzimidazol-2-one were repeated except that2,3-dihydrobenzoxazol-2-one was used in place of2,3-dihydrobenzimidazol-2-one. There were thus obtained3-methyl-2,3-dihydrobenzoxazol-2-one in 63% yield, m.p. 80°-82° C.; and6-iodo-3-methyl-2,3-dihydrobenzoxazol-2-one in 36% yield, m.p. 184°-185°C.

EXAMPLE 4

A solution of potassium peroxymonosulphate (0.32 g) in water (2 ml) wasadded to a solution of4-[3-(1,3-dimethyl-2-oxo-2,3-dihydrobenzimidazol-5-ylthio)phenyl]-4-methoxytetrahydropyran(0.125 g) in ethanol (2 ml) and the resultant mixture was stirred atambient temperature for 66 hours. The mixture was partitioned betweenmethylene chloride and water. The organic phase was washed with water,dried (MgSO₄) and evaporated. The residue was purified by columnchromatography using ethyl acetate as eluent. There was thus obtained4-[3-(1,3-dimethyl-2-oxo-2,3-dihydrobenzimidazol-5-ylsulphonyl)phenyl]-4-methoxytetrahydropyran(0.094 g, 69%), m.p. 214°-215° C.

NMR Spectrum (CDCl₃, δ values) 1.9-2.05 (m, 4H), 2.95 (s, 3H), 3.45 (2s's, 6H), 3.8-3.9 (m, 4H), 7.0-8.0 (m, 7H).

EXAMPLE 5

Using a similar procedure to that described in Example 4,4-methoxy-4-[3-(3-methyl-2-oxo-2,3-dihydrobenzothiazol-6-ylthio)phenyl]tetrahydropyranwas oxidised with potassium peroxymonosulphate to give4-methoxy-4-[3-(3-methyl-2-oxo-2,3-dihydrobenzothiazol-6-ylsulphonyl)phenyl]tetrahydropyranin 75% yield, m.p. 174°-176° C.

NMR Spectrum CDCl₁₃, & values) 1.85-2.05 (m, 4H), 2.95 (s, 3H), 3.5 (s,3H), 3.8-3.9 (m, 4H), 7.1-8.05 (m, 7H).

EXAMPLE 6

Using a similar procedure to that described in Example 4,4-methoxy-4-[3-(3-methyl-2-oxo-2,3-dihydrobenzoxazol-6-ylthio)phenyl]tetrahydropyranwas oxidised with potassium peroxymonosulphate to give4-methoxy-4-[3-(3-methyl-2-oxo-2,3-dihydrobenzoxazol-6-ylsulphonyl)phenyl]tetrahydropyranin 73% yield, m.p. 163°-165° C.

NMR Spectrum CDCl₃, δ values) 1.9-2.1 (m, 4H), 2.95 (s, 3H), 3.4 (s,3H), 3.8-3.9 (m, 4H), 7.1-8.0 (m, 7H).

EXAMPLE 7

A mixture of 6-bromomethyl-3-methyl-2,3-dihydrobenzothiazol-2-one (0.36g), 4-(5-fluoro-3-hydroxyphenyl)-4-methoxytetrahydropyran (0.3 g),potassium carbonate (0.276 g) and DMF (5 ml) was stirred at ambienttemperature for 16 hours. The mixture was poured onto a mixture of iceand water (10 ml) and extracted with ethyl acetate. The organic phasewas washed with brine, dried (MgSO₄) and evaporated. The residue wastriturated in a mixture of diethyl ether and hexane. There was thusobtained4-[5-fluoro-3-(3-methyl-2-oxo-2,3-dihydrobenzothiazol-6-ylmethoxy)phenyl]-4-methoxytetrahydropyran(0.414 g, 77%), m.p. 104°-106° C.

NMR Spectrum CDCl₃, δ values) 1.9-2.0 (m, 4H), 3.0 (s, 3H), 3.5 (s, 3H),3.8-3.9 (m, 4H), 5.05 (s, 2H), 6.6-6.8 (m, 3H), 7.0-7.1 (m, 1H), 7.4 (m,1H), 7.5 (d, 1H).

The 6-bromomethyl-3-methyl-2,3-dihydrobenzothiazol-2-one used as astarting material was obtained as follows:

1,1'-Carbonyldiimidazole (2 g) was added to a suspension of2-amino-5-methylphenylthiol (1.39 g; J. Chem. Soc. (C), 1969, 2148) inTHF (40 ml) which had been cooled in an ice-bath. The mixture wasstirred for 16 hours and allowed to warm to ambient temperature. Themixture was evaporated. The residue was triturated in a mixture ofdiethyl ether and water to give 6-methyl-2,3-dihydrobenzothiazol-2-one(0.57 g, 36%), m.p. 163°-166° C. The mother liquors were evaporated andthe resultant residue was partitioned between ethyl acetate and water.The organic phase was washed with brine, dried (MgSO₄) and evaporated.The residue was triturated in diethyl ether. There was thus obtained asecond crop of the benzothiazol-2-one (0.4 g, 24%).

Sodium hydride (55% dispersion in oil, 0.26 g) was added to a mixture ofthe product so obtained (0.95 g) and DMF (10 ml) which had been cooledin an ice-water bath. The mixture was stirred at O° C. for 1.5 hours andthen cooled to -20° C. Methyl iodide (0.85 g) in DMF (4 ml) was addeddropwise and the mixture was stirred for 3 hours and allowed to warm to5° C. The mixture was partitioned between cold dilute hydrochloric acidand ethyl acetate. The organic phase was washed with water and brine,dried (MgSO₄) and evaporated. The residue was purified by columnchromatography using a 19:1 v/v mixture of toluene and ethyl acetate aseluent. There was thus obtained3,6-dimethyl-2,3-dihydrobenzothiazol-2-one (0.85 g, 83%), m.p. 70°-71°C.

A mixture of the product so obtained (0.83 g), N-bromosuccinimide (0.87g), azobisisobutyronitrile (0.01 g) and carbon tetrachloride (20 ml) wasstirred and heated to reflux for 2 hours. The mixture was cooled toambient temperature and partitioned between methylene chloride andwater. The organic phase was dried (MgSO₄) and evaporated. There wasthus obtained 6-bromomethyl-3-methyl-2,3-dihydrobenzothiazol-2-one (0.8g, 67%), m.p. 146°-149° C.

NMR Spectrum CDCl₃, δ values) 3.45 (s, 3H), 4.5 (s, 2H), 7.0 (d, 1H),7.3-7.4 (m, 1H), 7.5 (d, 1H).

The 4-(5-fluoro-3-hydroxyphenyl)-4-methoxytetrahydropyran used as astarting material was obtained as follows:

Sodium hydride (50% w/w dispersion in mineral oil, 12.4 g) was addedportionwise to a mixture of benzyl alcohol (26.7 ml) and DMA (500 ml)and the mixture was stirred at ambient temperature for 1 hour.1-Bromo-3,5-difluorobenzene (50 g) was added carefully to control thevigour of the ensuing exothermic reaction. The mixture was stirred atambient temperature for 2 hours and the solvent was evaporated. Theresidue was partitioned between methylene chloride and water and theorganic phase was washed with water (4×50 ml), dried (MgSO₄) andevaporated. The residue was purified by distillation to give3-benzyloxy-1-bromo-5-fluorobenzene (41.8 g, 57%), as a colourlessliquid (b.p. 124°-130° C. at 0.3 mm Hg).

A solution of a portion (9.75 g) of this product in THF (150 ml) wascooled to -75° C. and n-butyl-lithium (1.6M in hexane, 22 ml) was addeddropwise. The mixture was stirred at -75° C. for 1 hour and a solutionof tetrahydropyran-4-one (3.47 g) in THF (10 ml) was added dropwise. Themixture was stirred at -75° C. for 1 hour and then allowed to warm to 0°C. A saturated aqueous ammonium chloride solution (50 ml) was added andthe organic phase was separated, dried (MgSO₄) and evaporated. Theresidue was purified by column chromatography using a 1:1 v/v mixture oftoluene and ethyl acetate as eluent. There was thus obtained4-(3-benzyloxy-5-fluorophenyl)-4-hydroxytetrahydropyran (7.4 g, 71%) asan oil.

After appropriate repetition of the above-mentioned reaction the productso obtained (12.1 g) was dissolved in THF (150 ml) and sodium hydride(50% w/w dispersion in mineral oil, 2.11 g) was added portionwise. Themixture was stirred at ambient temperature for 1 hour, cooled in anice-bath and methyl iodide (3.75 ml) was added dropwise. The mixture wasstirred at ambient temperature for 18 hours, 2N aqueous hydrochloricacid (3 drops) was added and the organic solvent was evaporated. Theresidue was partitioned between ethyl acetate and water. The organicphase was separated, washed with water and with brine, dried (MgSO₄) andevaporated. There was thus obtained4-(3-benzyloxy-5-fluorophenyl)-4-methoxytetrahydropyran (12.5 g, 99%),as a pale yellow oil which was used without further purification.

A solution of the product so obtained in ethanol (100 ml) washydrogenated in the presence of 10% palladium-on-charcoal catalyst for 3hours. The mixture was filtered and the filtrate was evaporated. Therewas thus obtained 4-(5-fluoro-3-hydroxyphenyl)-4-methoxytetrahydropyran(7.7 g, 86%), m.p. 123°-124° C.

EXAMPLE 8

The procedure described in Example 7 was repeated except that6-bromomethyl-3-methyl-2,3-dihydrobenzoxazol-2-one was used in place of6-bromomethyl-3-methyl-2,3-dihydrobenzothiazol-2-one. There was thusobtained4-[5-fluoro-3-(3-methyl-2-oxo-2,3-dihydrobenzoxazol-6-ylmethoxy)phenyl]-4-methoxytetrahydropyranin 80% yield, m.p. 139°-141° C.

NMR Spectrum CDCl₃, δ values) 1.9-2.0 (m, 4H), 3.0 (s, 3H), 3.4 (s, 3H),3.8-3.9 (m, 4H), 5.1 (s, 2H), 6.6-6.8 (m, 3H), 7,0 (m, 1H), 7.2-7.3 (m,2H).

The 6-bromomethyl-3-methyl-2,3-dihydrobenzoxazol-2-one used as astarting material was obtained as follows:

The procedures described in the second and third paragraphs of theportion of Example 7 which is concerned with the preparation of6-bromomethyl-3-methyl-2,3-dihydrobenzothiazol-2-one were repeatedexcept that 6-methyl-2,3-dihydrobenzoxazol-2-one (J. Het. Chem., 1982,19, 1545) was used in place of 6-methyl-2,3-dihydrobenzothiazol-2-one.There were thus obtained inturn:-3,6-dimethyl-2-oxo-2,3-dihydrobenzoxazol-2-one in 80% yield, m.p.108°-110° C.; and 6-bromomethyl-3-methyl-2,3-dihydrobenzoxazol-2-one in80% yield, m.p. 145°-150° C.,

NMR Spectrum (CDCl₃, δ values) 3.4 (s, 3H), 4.55 (s, 2H), 6.9 (d, 1H),7.2-7.3 (m, 2H).

EXAMPLE 9

The procedure described in Example 7 was repeated except that6-bromo-5-bromomethyl-1,3-dimethyl-2,3-dihydrobenzimidazol-2-one wasused in place of 6-bromomethyl-3-methyl-2,3-dihydrobenzoxazol-2-one.There was thus obtained4-[3-(6-bromo-1,3-dimethyl-2-oxo-2,3-dihydrobenzimidazol-5-ylmethoxy)-5-fluorophenyl]-4-methoxytetrahydropyranin 50% yield, m.p. 161°-162° C.

NMR Spectrum CDCl₃, δ values) 1.9-2.1 (m, 4H), 3.0 (s, 3H), 3.4 (s, 6H),3.8-3.9 (m, 4H), 5.2 (s, 2H), 6.6-6.9 (m, 3H), 7.15 (s, 1H), 7.2 (s,1H).

The 6-bromo-5-bromomethyl-1,3-dimethyl-2,3-dihydrobenzimidazol-2-oneused as a starting material was obtained as follows: The proceduresdescribed in the first and second paragraphs of the portion of Example 7which is concerned with the preparation of6-bromomethyl-3-methyl-2,3-dihydrobenzothiazol-2-one were repeatedexcept that 3,4-diaminotoluene was used in place of2-amino-5-methylphenylthiol. There were thus obtained in turn:-5-methyl-2,3-dihydrobenzimidazol-2-one in 75% yield, m.p. >250° C.; and1,3,5-trimethyl-2,3dihydrobenzimidazol-2-one in 77% yield, m.p. 102° C.

A mixture of the product so obtained (1.4 g), N-bromosuccinimide (1.5g), azobisisobutyronitrile (5 mg) and carbon tetrachloride (30 ml) wasstirred and heated to reflux. A second portion (5 mg) ofazobisisobutyronitrile was added and the mixture was maintained atreflux for 1.5 hours. The mixture was cooled to ambient temperature andpartitioned between methylene chloride and water. The organic phase waswashed with water, dried (MgSO₄) and evaporated. The solid residue waswashed with diethyl ether and dried. There was thus obtained 6-bromo-1,3,5-trimethyl-2,3-dihydrobenzimidazol-2-one (0.4 g, 69%), m.p. 132°-137°C.

The product so obtained was treated with N-bromosuccinimide using theprocedure described immediately above. There was thus obtained6-bromo-5-bromomethyl-1,3-dimethyl-2,3-dihydrobenzimidazol-2-one in 84%yield, as a solid.

NMR Spectrum (CDCl₃, δ values) 3.4 (2 s's, 6H), 4.7 (s, 2H), 7.05 (s,1H), 7.26 (s, 1H).

EXAMPLE 10

A mixture of4-[3-(6-bromo-1,3-dimethyl-2-oxo-2,3-dihydrobenzimidazol-5-ylmethoxy)-5-fluorophenyl]-4-methoxytetrahydropyran(0.19 g), sodium formate (0.06 g), tetrakis(triphenylphosphine)palladium(0.047 g) and DMF (2 ml) was heated to 100° C. for 2 hours. Equivalentamounts of sodium formate and the palladium catalyst were addedportionwise over the following 4 hours as the mixture was maintained ata temperature of 100° C. The mixture was cooled to ambient temperatureand partitioned between ethyl acetate and water. The organic phase waswashed with water and with brine, dried (MgSO₄) and evaporated. Theresidue was purified by column chromatography using a 5:3 v/v mixture oftoluene and ethyl acetate as eluent. The product so obtained wastriturated in diethyl ether. The solid so obtained was filtered off anddried. There was thus obtained4-[5-fluoro-3-(1,B-dimethyl-2-oxo-2,3-dihydrobenzimidazol-5-ylmethoxy)phenyl-4-methoxytetrahydropyran(0.09 g, 57%), m.p. 136°-137° C.

NMR Spectrum CDCl₃, values) 1.9-2.0 (m, 4H), 3.0 (s, 3H), 3.45 (2 s's,6H), 3.8-3.9 (m, 4H), 5.1 (s, 2H), 6.6-6.8 (m, 3H), 7.0-7.2 (m, 3H).

EXAMPLE 11

The procedure described in Example 1 was repeated except that5-iodo-1,3,3-trimethylindolin-2-one was used in place of5-iodo-1,3-dimethyl-2,3-dihydrobenzimidazol-2-one. The crude product soobtained was purified by column chromatography using increasingly polarmixtures of hexane and ethyl acetate as eluent. The product so obtainedwas further purified by column chromatography on reverse phase silicausing decreasingly polar mixtures of methanol and water as eluent. Therewas thus obtained4-methoxy-4-[3-(1,3,3-trimethyl-2-oxoindolin-5-ylthio)phenylltetrahydropyranin 23% yield, m.p. 132°-134° C.

NMR Spectrum CDCl₃, δ values) 1.35 (s, 6H), 1.85-2.05 (m, 4H), 2.95 (s,3H), 3.25 (s, 3H), 3.75-3.85 (m, 4H), 6.85 (d, 1H), 7.1 (m, 1H),7.18-7.3 (m, 4H), 7.4 (m, 1H).

The 5-iodo-1, 3,3-trimethylindolin-2-one used as a starting material wasobtained as follows:

The procedure described in the last paragraph of the portion of Example1 which is concerned with the preparation of5-iodo-1,3-dimethyl-2,3-dihydrobenzimidazol-2-one was repeated exceptthat 1,3,3-trimethylindorin-2-one (J. Amer. Chem. Soc., 1934, 56, 1797)was used as the starting material. There was thus obtained the requiredstarting material in 76% yield, m.p. 153°-154° C.

NMR Spectrum CDCl₃, δ values) 1.45 (s, 6H), 3.2 (s, 3H), 6.54 (d, 1H),7.48 (d, lb), 7.6 (d of d's, 1H).

EXAMPLE 12

Using a similar procedure to that described in Example 4,4-methoxy-4-[3-(1,3,3-trimethyl-2-oxoindolin-5-ylthio)phenyl]tetrahydropyranwas oxidised with potassium peroxymonosulphate to give4-methoxy-4-[3-(1,3,3-trimethyl-2-oxoindolin-5-ylsulphonyl)phenyl]tetrahydropyranin 80% yield, m.p. 164°-166° C.

NMR Spectrum CDCl₃, δ values) 1.48 (s, 6H), 1.88-2.10 (m, 4H), 2.95 (s,3H), 3.25 (s, 3H), 3.8-3.9 (m, 4H), 6.9 (d, 1H), 7.55 (m, 1H), 7.6 (m,1H), 7.75 (m, 1H), 7.85 (m, 1H)., 7.90.(m, 1H), 7.95 (m, 1H).

EXAMPLE 13

The procedure described in Example 7 was repeated except that5-bromomethyl-1,3,3-trimethylindolin-2-one was used in place of6-bromomethyl-3-methyl-2,3-dihydrobenzothiazol-2-one. The crude productso obtained was purified by column chromatography on alumina using a 4:1v/v mixture of methylene chloride and acetone as eluent. There was thusobtained4-[5-fluoro-3-(1,3,3-trimethyl-2-oxoindolin-5-ylmethoxy)phenyl]-4-methoxytetrahydropyranin 17% yield, m.p. 124°-126° C.

The 5-bromomethyl-1,3,3-trimethylindolin-2-one used as a startingmaterial was obtained as follows:

A mixture of 1,3,3,5-tetramethylindolin-2-one (0.378 g; Chem. Abs.,1971, 77, 116019g), N-bromosuccinimide (0.484 g), benzoyl peroxide (0.01g) and carbon tetrachloride (10 ml) was stirred and irradiated with thelight from a 250 Watt lamp. The mixture was heated to 40° C. for 75minutes. The mixture was cooled to ambient temperature, petroleum ether(b.p. 40°-60° C.) was added and the mixture was filtered. The filtratewas evaporated to give the required starting material as-an oil (0.65 g,70%) which was used without further purification.

EXAMPLE 14

The procedure described in Example-7 was repeated except that5-bromomethyl-1-methylindolin-2,3-dione was used in place of6-bromomethyl-3-methyl-2,3-dihydrobenzothiazol-2-one. The crude productwas purified by column chromatography using increasingly polar mixturesof methylene chloride and diethyl ether as eluent. There was thusobtained4-]5-fluoro-3-(1-methyl-2,3-dioxoindolin-5-ylmethoxy)phenyl]-4-methoxytetrahydropyranin 75% yield, m.p. 138°-140° C.

The 5-bromomethyl-1-methylindolin-2,3-dione used as a starting materialwas obtained from 1,5-dimethylindolin-2,3-dione (Chem. Abs., 1983, 99,105082a) using a similar procedure to that described in the portion ofExample 13 which is concerned with the preparation of starting materialsexcept that the reaction mixture was heated to reflux for 1 hour. Therewas thus obtained the required starting material in 58% yield as a solidwhich was used without further purification.

EXAMPLE 15

Water (approximately 4 ml) was added dropwise to a solution of4-[5-fluoro-3-(1-methyl-2,3-dioxoindolin-5-ylmethoxy)phenyl]-4-methoxytetrahydropyran(0.16 g) in 1,4-dioxane (3 ml) until a solid began to be precipitated.The mixture was heated to reflux and sodium dithionite (0.143 g) wasadded in four portions over 15 minutes and after each addition water (1ml) was added to wash all of the dithionite into the reaction mixture.The reaction mixture was cooled and poured into water. The mixture wasextracted with diethyl ether and then with ethyl acetate. The combinedextracts were washed with water and brine, dried (MgSO₄) and evaporated.The residue was purified by column chromatography using a 19:1 v/vmixture of methylene chloride and methanol as eluent. There was thusobtained4-[5-fluoro-3-(3-hydroxy-1-methyl-2-oxoindolin-5-ylmethoxy)phenyl]-4-methoxytetrahydropyran(0.126 g, 73%), m.p. 134°-139° C. (recrystallised from diethyl ether).

EXAMPLE 16

Using a similar procedure to that described in Example 1,5-iodo-1,3-dimethyl-2,3-dihydrobenzimidazol-2-one was reacted4-(5-fluoro-3-mercaptophenyl)-4-methoxytetrahydropyran to give4-[3-(1,3-dimethyl-2-oxo-2,3-dihydrobenzimidazol-5-ylthio)-5-fluorophenyl]-4-methoxytetrahydropyranin 60% yield, m.p. 128°-130° C.

The 4-(5-fluoro-3-mercaptophenyl)-4-methoxytetrahydropyran, used as astarting material, is described in European Patent Application No.0420511 (Example 4 thereof).

EXAMPLE 17

Diethylaminosulphur trifluoride (0.082 ml) was added dropwise to-astirred solution of4-[5-fluoro-3-(1-methyl-2,3-dioxoindol-5-ylmethoxy)phenyl]-4-methoxytetrahydropyran(0.1 g) in a mixture of methylene chloride (2.5 ml) andfluorotrichloromethane (2.5 ml) which had been cooled to 0° C. Themixture was allowed to warm to ambient temperature and stirred at thistemperature for 16 hours. The mixture was evaporated and the residue waspurified by column chromatography using increasingly polar mixtures ofmethylene chloride and diethyl ether as eluent. There was thus obtained4-[5-fluoro-3-(3,3-difluoro-1-methyl-2-oxoindolin-5-ylmethoxy)phenyl]-4-methoxytetrahydropyran(0.03 g, 29%), as a foam which crystallised on trituration under diethylether, m.p. 151° C.

EXAMPLE 18

The following illustrate representative pharmaceutical dosage formscontaining the compound of formula I, or a pharmaceutically-acceptablesalt thereof (hereafter compound X), for therapeutic of prophylactic usein humans:

    ______________________________________                                        (a) Tablet I              mg/tablet                                           ______________________________________                                            Compound X            100                                                     Lactose Ph.Eur        182.75                                                  Croscarmellose sodium 12.0                                                    Maize starch paste (5% w/v paste)                                                                   2.25                                                    Magnesium stearate    3.0                                                 ______________________________________                                        (b) Tablet II             mg/tablet                                           ______________________________________                                            Compound X            50                                                      Lactose Ph.Eur        223.75                                                  Croscarmellose sodium 6.0                                                     Maize starch          15.0                                                    Polyvinylpyrrolidone (5% w/v paste)                                                                 2.25                                                    Magnesium stearate    3.0                                                 ______________________________________                                        (c) Tablet III            mg/tablet                                           ______________________________________                                            Compound X            1.0                                                     Lactose Ph.Eur        93.25                                                   Croscarmellose sodium 4.0                                                     Maize starch paste (5% w/v paste)                                                                   0.75                                                    Magnesium stearate    1.0                                                 ______________________________________                                        (d) Capsule               mg/capsule                                          ______________________________________                                            Compound X            10                                                      Lactose Ph.Eur        488.5                                                   Magnesium stearate    1.5                                                 ______________________________________                                        (e) Injection I           (50 mg/ml)                                          ______________________________________                                            Compound X            5.0% w/v                                                1M Sodium hydroxide solution                                                                        15.0% v/v                                               0.1M Hydrochloric acid                                                        (to adjust pH to 7.6)                                                         Polyethylene glycol 400                                                                             4.5% w/v                                                Water for injection to 100%                                               ______________________________________                                        (f) Injection II          (10 mg/ml)                                          ______________________________________                                            Compound X            1.0% w/v                                                Sodium phosphate BP   3.6% w/v                                                0.1M Sodium hydroxide solution                                                                      15.0% v/v                                               Water for injection to 100%                                               ______________________________________                                                                   (1 mg/ml,                                          (g) Injection III         buffered to pH6)                                    ______________________________________                                            Compound X            0.1% w/v                                                Sodium phosphate BP   2.26% w/v                                               Citric acid           0.38% w/v                                               Polyethylene glycol 400                                                                             3.5% w/v                                                Water for injection to 100%                                               ______________________________________                                        (h) Aerosol I             mg/ml                                               ______________________________________                                            Compound X            10.0                                                    Sorbitan trioleate    13.5                                                    Trichlorofluoromethane                                                                              910.0                                                   Dichlorodifluoromethane                                                                             490.0                                               ______________________________________                                        (i) Aerosol II            mg/ml                                               ______________________________________                                            Compound X            0.2                                                     Sorbitan trioleate    0.27                                                    Trichlorofluoromethane                                                                              70.0                                                    Dichlorodifluoromethane                                                                             280.0                                                   Dichlorotetrafluoroethane                                                                           1094.0                                              ______________________________________                                        (j) Aerosol III           mg/ml                                               ______________________________________                                            Compound X            2.5                                                     Sorbitan trioleate    3.38                                                    Trichlorofluoromethane                                                                              67.5                                                    Dichlorodifluoromethane                                                                             1086.0                                                  Dichlorotetrafluoroethane                                                                           191.6                                               ______________________________________                                        (k) Aerosol IV            mg/ml                                               ______________________________________                                            Compound X            2.5                                                     Soya lecithin         2.7                                                     Trichlorofluoromethane                                                                              67.5                                                    Dichlorodifluoromethane                                                                             1086.0                                                  Dichlorotetrafluoroethane                                                                           191.6                                               ______________________________________                                    

Note

The above formulations may be obtained by conventional procedures wellknown in the pharmaceutical art. The tablets (a)-(c) may be entericcoated by conventional means, for example to provide a coating ofcellulose acetate phthalate. %he aerosol formulations (h)-(k) may beused in conjunction with standard, ,metered dose aerosol dispensers, andthe suspending agents sorbitan trioleate and soya lecithin may bereplaced by an alternative suspending agent such as sorbitan monooleate,sorbitan sesquioleate, polysorbate 80, polyglycerol oleate or oleicacid. ##STR2##

What we claim is:
 1. A bicyclic heterocyclic derivative of the formulaIwherein Q is a benzoxazolyl or a hydrogenated derivative thereof whichsubstitutent Q may optionally bear one or two oxo or thioxo substituentsand up to four further substituents selected from halogeno, hydroxy,cyano, amino, (1-4C)alkyl, (1-4C)alkoxy, fluoro-(1-4C)alkyl,(1-4C)alkylamino; di-[(1-4C)alkyl]amino, amino-(1-4C)alkyl,(1-4C)alkylamino-(1-4C)alkyl, di-[(1-4C)alkyl]amino-(1-4C)alkyl, phenyland phenyl-(1-4C)alkyl, and wherein said phenyl or phenyl-(1-4C)alkylsubstituent may optionally bear a substituent selected from halogeno,(1-4C)alkyl and (1-4C)alkoxy; wherein A¹ is a direct link to X¹ or is(1-3C)alkylene; wherein X¹ is oxy, thio, sulphinyl, sulphonyl or imino;wherein Ar is phenylene which may optionally bear one or twosubstituents selected from halogeno, hydroxy, amino, nitro, cyano,carbamoyl, ureido, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino,di-[(1-4C)alkylamino, fluoro-(1-4C)alkyl and (2-4C)alkanoylamino;wherein R¹ is (1-4C)alkyl, (3-4C)alkenyl or (3-4C)alkynyl; and whereinR² and R³ together form a group of the formula --A² --X² --A³ -- which,together with the carbon atom to which A² and A³ are attached, defines aring having 5 to 7 ring atoms, wherein A² and A³ which may be the sameor different, each is (1-3C)alkylene and X² is oxy, thio, sulphinyl orsulphonyl, and which ring may bear one, two or three substituents, whichmay be the same or different, selected from hydroxy, (1-4C)alkyl and(1-4C)alkoxy; or wherein R¹ and R² together form a group of the formula--A² --X² --A³ -- which, together with the oxygen atom to which A² isattached and with the carbon atom to which A³ is attached, defines aring having 5 to 7 ring atoms, wherein A² and A³ which may be the sameor different, each is (1-3C)alkylene and X² is oxy, thio, sulphinyl orsulphonyl, and which ring may bear one, two or three (1-4C)alkylsubstituents, and wherein R³ is (1-4C)alkyl, (2-4C)alkenyl or(2-4C)alkynyl; or a pharmaceutically-acceptable salt thereof.
 2. Abicyclic heterocyclic derivative of the formula I as claimed in claim1wherein Q is benzoxazolyl or 2,3-dihydrobenzoxazolyl, which mayoptionally bear one or two oxo or thioxo substituents and up to foursubstituents selected from fluoro, chloro, bromo, hydroxy, cyano, amino,methyl, ethyl, propyl, methoxy, trifluoromethyl, 2-fluoroethyl,2,2,2-trifluoroethyl, 2-methylaminoethyl, 2-dimethylaminoethyl, phenyland benzyl, and wherein said phenyl or benzyl substituent may optionallybear a substituent selected from chloro, methyl and methoxy; A¹ is adirect link to X¹ or is methylene; X¹ is oxy, thio, sulphinyl orsulphonyl; Ar is 1,3-phenylene or 1,4-phenylene which may optionallybear one or two substituents selected from fluoro, chloro, hydroxy,amino, nitro, ureido, methoxy, dimethylamino, trifluoromethyl andacetamido; R¹ is methyl, ethyl, allyl or 2-propynyl; and R² and R³together form a group of the formula --A² --X² --A³ -- which, togetherwith the carbon atom to which A² and A³ are attached, defines a ringhaving 5 or 6 ring atoms, wherein A² is ethylene, A³ is methylene orethylene, and X² is oxy, and which ring may bear one or two substituentsselected from methyl, ethyl, propyl, methoxy and ethoxy; or R¹ and R²together form a group of the formula --A² --X² --A³ -- which, togetherwith the oxygen atom to which A² is attached and with the carbon atom towhich A³ is attached, defines a ring having 5 or 6 ring atoms, whereinA² is methylene, A³ is methylene or ethylene, and X² is oxy, and whichring may bear one, two or three substituents selected from methyl, ethyland propyl, and R³ is methyl or ethyl; or a pharmaceutically-acceptablesalt thereof.
 3. A bicyclic heterocyclic derivative of the formula I asclaimed in claim 1wherein Q is 2-oxo-2,3-dihydrobenzoxazol-6-yl whichmay optionally bear one, two or three substituents selected from fluoro,chloro, hydroxy, methyl, ethyl, propyl, 2-fluoroethyl,2-dimethylaminoethyl, phenyl and benzyl; A¹ is a direct link to X¹, oris methylene; X¹ is oxy, thio, sulphinyl or sulphonyl; Ar is1,3-phenylene or 1,4-phenylene which may optionally bear one or twosubstituents selected from fluoro, hydroxy, amino, nitro, ureido,methoxy, dimethylamino, trifluoromethyl and acetamido; R¹ is methyl,ethyl, allyl or 2-propynyl; and R² and R³ together form a group of theformula --A² --X² --A³ -- which, together with the carbon atom to whichA² and A³ are attached, defines a ring having 5 or 6 ring atoms, whereinA² is ethylene, is A³ is methylene or ethylene, and X² is oxy, and whichring may bear one or two substituents selected from methyl and ethyl; orR¹ and R² together form a group of the formula --A² --X² --A³ -- which,together with the oxygen atom to which A² is attached and with thecarbon atom to which A³ is attached, defines a ring having 5 ring atoms,wherein A² is methylene, A³ is methylene, and X² is oxy, and which ringmay bear one, two or three substituents selected from methyl and ethyl,and R³ is methyl or ethyl; or a pharmaceutically-acceptable saltthereof.
 4. A pharmaceutical composition which comprises a bicyclicheterocyclic derivative of the formula I, or apharmaceutically-acceptable salt thereof, as claimed in any one ofclaims 1 to 3 in association with a pharmaceutically-acceptable diluentor carrier.
 5. A method of treating a disease or medical conditionmediated alone or in part by one or more leukotrienes which comprisesadministering to a warm-blooded animal requiring such treatment aneffective amount of a bicyclic heterocyclic derivative of the formula I,or a pharmaceutically-acceptable salt thereof, as claimed in any one ofclaims 1 to 3.